Abstract: The overall goal of this new application for a Midcareer Investigator Award in Patient-Oriented Research is to enable Dr. Lee to build a research and mentoring program in patient-oriented research in acute lung injury and host defense. Acute lower respiratory traction infections (LRTI) in the ICU remains an enormous healthcare burden in the US and worldwide. LRTI remains a major cause of sepsis and risk factor for acute lung injury. Bacterial LRTI is also a frequent complication of acute lung injury that increases patient morbidity, length of stay and health-care costs. Dr. Lee is a physician scientist focused on broadening molecular understanding of critical illness syndromes such as acute lung injury by probing host-pathogen interplay to elucidate the biology of host factors that predispose individuals to pathogen-induced injury. This award will allow protected time for dedicated teaching, training, and mentoring of trainees that include junior faculty, fellows, residents, and medical students in translational research focusing on problems arising in critically ill patients. Specifically, mentoring will support novel investigations into acute lower respiratory tract infections from common Gram-negative bacterial pathogens in the ICU. The major hypothesis is that distinct molecular determinants of host-pathogen interplay identified at the bench provide unique insights into impairments of host defense mechanisms that associate with adverse clinical outcomes in the ICU. Two aims are proposed that leverage the unique capabilities of the investigator in translational research. Aim 1 will evaluate microbial factors that predispose patients to tissue inflammation and injury instigated by the Gram-negative pathogen Pseudomonas aeruginosa (PA) respiratory isolates in the ICU. We will test molecular pathways identified at the bench to explore the relationship between pathogen protease function to patient outcomes such as microbial persistence in the lower respiratory tract, ventilator-free days, length of stay and mortality. Aim 2 will evaluate impairments in host humoral immunity during critical illness and examine the relationship to patient outcomes including multiple organ dysfunction, mortality, acquisition of multi-drug resistant ICU infections, and serum killing of encapsulated Gram-negative pathogen Klebsiella pneumoniae. This K24 award will allow Dr. Lee to achieve two principal goals: (1) forge links between basic biology and medicine by probing host-pathogen interplay in the ICU setting and improve understanding of critical illness syndromes such as ARDS; and (2) to further develop her skills in mentoring trainees in patient-oriented research in molecular critical care while expanding her time devoted to mentoring. The successful execution of this award will enhance the productivity of both the K24 investigator and increase the pool of well-trained clinician investigators who are equipped to translate fundamental biology to the bedside and back.